Interferon has been used as a therapeutic agent for hepatitis, and commercialized as interferon-alpha formulations (e.g., Intron-A; Schering and Roferon-A; Roche) and PEGylated IFN formulations (e.g., PEG-Intron: Schering, Pegasys: Roche) having reduced numbers of administration than interferon-alpha formulation.
Examples of initial side effects of interferon-alpha treatment include fever, chills, asthenia universalis, anorexia, nausea and myalgia. As these symptoms appear in a dose dependent manner in most of patients, side effects are most severe at the early stage of treatment, and normally disappear after the end of treatment. Further, it has been known that frequency and severity of side effects during PEG-interferon-alpha treatment are similar to those of interferon-alpha treatment (see Kwan Sik Lee, Dong Joon Kim et al. Management of Chronic Hepatitis B, The Korean Journal of Hepatology. 13:447-488, (2007)).
As above, since side effects depending on administration dose of interferon have been known, reduction in administration dose is required to minimize side effects when interferon is used as a therapeutic agent.
Conventionally, to solve problems described above, a cytoplasmic transduction peptide (CTP) is fused with interferon thereby improving an ability of interferon to migrate into liver to provide a tool for resolving side effects of interferon alpha treatment. However, when the fusion protein is administered to a mouse model, the initial activity is rapidly decreased such that at least half of the activity is decreased after 6 hours. Thus, a need has been emerged to improve the retention property and the ability to migrate to liver of the fusion protein.
Throughout the specification, numerous journals and patent documents are referenced, and the citation is indicated. Disclosures of cited journals and patent documents are incorporated herein in their entireties by reference to more clearly describe the level of the technical field to which the present invention belongs and features of the present invention.